Highlighting the Promise of Ruxolitinib in Patients With Polycythemia Vera and Myelofibrosis

Jean-Jacques Kiladjian, MD, PhD, discusses 2 clinical trials evaluating the use of ruxolitinib in patients with polycythemia vera and myelofibrosis.

Ruxolitinib (Jakafi) has demonstrated promise as a treatment for patients with polycythemia vera (PV) who are resistant or intolerant to hydroxyurea, as well as in combination with pegylated interferon alfa-2a (Pegasys) for patients with myelofibrosis (MF), according to findings from 2 recent clinical trials.

Five-year follow-up findings from the RESPONSE trial showed durable efficacy and safety with ruxolitinib compared with best available therapy in patients with hydroxyurea-resistant/intolerant PV.

For patients with MF, ruxolitinib has been shown to provide benefit, but it does not show effects on the disease history. Pegylated interferon alfa-2a has also shown to be effective in treating patients with MF, but it is associated with a high toxicity profile. The RUXOPeg trial aims to safely combine these 2 agents, with preliminary findings showing the combination appears well-tolerated and effective.

In an interview withTargeted Oncologyduring the 2018 ASH Annual Meeting, lead investigator, Jean-Jacques Kiladjian, MD, PhD, professor of clinical pharmacology at Paris Diderot University, discussed the results from these 2 clinical trials and how they will impact the treatment of patients with PV and MF.

TARGETED ONCOLOGY:Can you begin by providing some background on the RESPONSE trial?

Kiladjian:The RESPONSE trial was a clinical study that assessed the role of ruxolitinib in patients with PV who were intolerant or resistant to hydroxyurea. These patients were randomized to ruxolitinib versus best available therapy.

The initial publication of the RESPONSE study results showed that ruxolitinib was clearly superior to best available therapy for achieving a control of the hematocrit in 30% to 40% [of patients] without phlebotomy and reduction in the spleen volume by more than 35%. Here at the ASH meeting, we present the long-term results of this study after approximately 5 years of follow-up in these patients.

TARGETED ONCOLOGY:What were the results from the 5-year follow-up?

Kiladjian:We were very pleased to see that after 5 years of follow-up, most of the patients remained on the drug. More than 65% of patients were still treated with ruxolitinib, and in addition, those who achieved the primary response maintained this response in more than 74% of cases up to 5 years of follow-up.

In addition, for complete clinicohematologic response, meaning patients with a hematocrit below 45% but also with normal platelets and normal lymphocyte counts, these patients also maintained their response. Fifty-four percent of them were still in complete clinicohematologic response after 5 years.

In addition, we were also pleased to see some molecular response was achieved since the meanJAK2-mutant burden was decreased by about 38% after 5 years compared to baseline, meaning that we can target the malignant clone with this drug. We see significant decrease in theJAK2-mutant burden.

TARGETED ONCOLOGY:Can you discuss the significance of these findings?

Kiladjian:For these patients with PV who are resistant to hydroxyurea, the outcome is usually very poor, and their life expectancy is clearly reduced with high risk of vascular complications and also transformation. Here, we have an opportunity to treat patients with a good efficacy and also with a good safety because we also found that the incidence of adverse events (AEs) decreased over time and we had less AEs during the last period of the study than in the beginning. Still, we have some particular AEs that have to be carefully followed. They are viral infections that are slightly more frequent in ruxolitinib-treated patients, especially zoster infection and also non-melanoma skin cancer, especially in those patients who had previous long exposure to hydroxyurea, and those who already had a history of pre-cancerous skin lesions.

TARGETED ONCOLOGY:What do you hope oncologists take away from these findings?

Kiladjian:It was important to us to see long-term maintenance of response with ruxolitinib, because for example, in MF patients on the clinical trials, we saw that the majority of patients had stopped the drug. Here, in PV, most of the patients can maintain their treatment with very good efficacy with also a very low toxicity. In addition, we also found that vascular events were less frequent in patients treated with ruxolitinib compared to those on the best available therapy arm, meaning that we may also influence the risk of vascular events in these patients and this is of course, a very important point for patients with PV.

TARGETED ONCOLOGY:Can you also share some background on the RUXOPeg trial?

Kiladjian:The RUXOPeg trial tested the combination of ruxolitinib and pegylated interferon alfa-2a in patients with MF. While we know that ruxolitinib provides clear benefit to patients with MF, it doesn’t clearly affect the disease history, at least on the short-term. On the other hand, interferon is a drug that has been shown consistently to reduce molecular response and clinicohematologic responses but has a high toxicity, mostly in new and inflammatory-mediated. The idea was to, maybe, use ruxolitinib and its anti-inflammatory properties to offset the toxicity of interferon and improve the rate of molecular response and clinicohematologic responses.

TARGETED ONCOLOGY:How was the study designed?

Kiladjian:The RUXOPeg study included patients with MF with intermediate- to high-risk categories according to International Prognostic Scoring System (IPSS) in need of an active therapy. The study design was a Bayesian multicenter trial with the first phase presented at ASH 2018 that aimed to test several dose combinations with 3 predefined doses of ruxolitinib — 10, 15, and 20 mg BID combined to treat with pegylated interferon doses of 45, 90, and 135 mcg per week. There were 9 possible combinations, and by design of this study, we were allowed to test 6 of these and reach the highest dose combination, meaning 20 mg ruxolitinib every day combined with 135 mcg of interferon per week.

TARGETED ONCOLOGY:What is the main takeaway from this study?

Kiladjian:We were very pleased to see the tolerance was very good since the primary tolerance criterion was the criteria of a dose-limiting toxicity. In the first 16 patients enrolled in this study, we have not seen any of these dose-limiting toxicities, so we will now proceed to the second part of the study which will randomize the 2 highest dose combinations and include a total of 42 patients, this time to assess the efficacy since the safety seems okay regarding the spleen response in particular.